Differential T cell response in central and peripheral nerve injury: connection with immune privilege

Moalem, Gila; Monsonego, Alon; Shani, Yael; Cohen, Irun R.; Schwartz, Michal

doi:10.1096/fasebj.13.10.1207

Cited by 144 publications

(88 citation statements)

References 57 publications

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“…Another common characteristic of injured CNS is the increased presence of infiltrating immune cells that have been suggested to contribute to the pathology and the spread of damage (2). However, some studies have shown that in the event of an acute injury or chronic neurodegenerative conditions, T cells are recruited by and accumulate in the CNS (41,42), where they rescue neurons from degeneration. Moreover, a well-controlled boost of autoimmune activity following injury increases the number of surviving neurons (43).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, l-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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“…The number of Cop-1-reactive T cells that home to the CNS is increased after CNS injury (55). It therefore seems likely that Cop-1-reactive T cells recognize self-antigens presented at the site of the lesion.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Angelov

Waibel

Guntinas‐Lichius

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

179

104

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Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu͞Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ؎ 7 days (n ‫؍‬ 15) to 263 ؎ 8 days (n ‫؍‬ 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

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“…Cop-1, acting as an immunogen, may serve both purposes-neuroprotection from neuronal insult and therapy for autoimmune diseases. Presumably it achieves this dual purpose by evoking a ''safe'' T cell response, which provides, on the one hand, the beneficial autoimmune T cell response needed for neuroprotection (1,2,7,23,24) and, on the other hand, the immune modulation required for avoidance of autoimmune disease (25).…”

Section: Discussionmentioning

confidence: 99%

“…R ecent studies in our laboratory demonstrated that the death of neurons after traumatic injury to the central nervous system (CNS) can be delayed and reduced by reinforcing a T cell immune response directed against myelin-associated self-antigens (1)(2)(3). With the use of optic nerve injury of adult rats as a model, we found that, irrespective of their antigen specificity, T cells accumulate at the lesion site after injury, and their numbers increase after their passive transfer (1,2,4).…”

mentioning

confidence: 88%

“…With the use of optic nerve injury of adult rats as a model, we found that, irrespective of their antigen specificity, T cells accumulate at the lesion site after injury, and their numbers increase after their passive transfer (1,2,4). We further demonstrated that passive transfer of T cells specific to myelin basic protein (MBP), but not to non-self-antigens, reduces the posttraumatic neuronal loss in rat models of optic nerve crush and spinal cord contusion (3,5).…”

mentioning

confidence: 94%

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Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

Schori

Kipnis

Yoles

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

275

181

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Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 ؎ 270 and 1,329 ؎ 121, respectively, mean ؎ SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 ؎ 101 compared with 1,414 ؎ 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% ؎ 6.8% to 4.3% ؎ 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.

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Differential T cell response in central and peripheral nerve injury: connection with immune privilege

Cited by 144 publications

References 57 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

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